Selective Uptake Research Articles

Three OsMYB36 members redundantly regulate Casparian strip formation at the root endodermis.

Plants have evolved a lignin-based Casparian strip (CS) in roots that restricts passive diffusion of mineral elements from the soil to the stele. However, the molecular mechanisms underlying CS formation in rice (Oryza sativa), which contains a CS at both the exodermis and endodermis, are poorly understood. Here, we demonstrate that CS formation at the rice endodermis is redundantly regulated by three MYELOBLASTOSIS (MYB) transcription factors, OsMYB36a, OsMYB36b, and OsMYB36c, that are highly expressed in root tips. Knockout of all three genes resulted in a complete absence of CS at the endodermis and retarded plant growth in hydroponic conditions and in soil. Compared with the wild-type, the triple mutants showed higher calcium (Ca) levels and lower Mn, Fe, Zn, Cu, and Cd levels in shoots. High Ca supply further inhibited mutant growth and increased Ca levels in shoots. Transcriptome analysis identified 1,093 downstream genes regulated by OsMYB36a/b/c, including the key CS formation gene OsCASP1 and other genes that function in CS formation at the endodermis. Three OsMYB36s regulate OsCASP1 and OsESB1 expression by directly binding to MYB-binding motifs in their promoters. Our findings thus provide important insights into the mechanism of CS formation at the endodermis and the selective uptake of mineral elements in roots.

Phenotype-genotype correlation in aldosterone-producing adenomas characterized by intracellular cholesterol metabolism

Aldosterone-producing adenoma (APA) is histologically composed of clear and compact tumor cells. KCNJ5- mutated APAs were reported to be associated with higher plasma aldosterone concentration and more abundant clear tumor cells containing lipid droplets than non-KCNJ5- mutated APAs. However, the association among cholesterol uptake and/or synthesis, cellular morphology and genotypes has remained unknown. Therefore, in order to explore these differences, 52 APA cases (KCNJ5 mt: n = 33, non-KCNJ5 mt: n = 19; ATP1A1: n = 3, ATP2B3: n = 3, CACNA1D: n = 5, CTNNB1: n = 1, tumors without any mutation above: n = 7), zona glomerulosa (ZG) tissue adjacent to APA and 10 non-pathological adrenal glands (NAs) were examined for quantitative histopathological analysis of tumor morphology and immunohistochemical analysis of cholesterol receptors (SR-B1, LDL-R), cholesterol metabolic enzymes (ACAT1, ACAT2, HSL, DHCR24, StAR), and the enzymes required for steroid synthesis (CYP11A1, CYP17A, 3βHSD, CYP11B1, CYP11B2). Gas chromatography-mass spectrometry (GC-MS) analysis was further performed to profile cholesterol precursors and metabolites in 21 APA cases (KCNJ5 mt: n = 16, non-KCNJ5 mt: n = 5) and 14 adrenal cortex of adjacent adrenal tissues. Results demonstrated that both SR-B1 and DHCR24 were significantly lower in the ZG than in fasciculata or reticularis of NAs but LDL-R was not significantly different among them in immunohistochemical analysis. SR-B1 and DHCR24 were both significantly higher in APAs than in ZG tissue adjacent to APA. In GC-MS analysis, most cholesterol precursors and metabolites, except for lanosterol, and their metabolic ratios (= concentration of cholesterol/ precursor) were higher in APAs than in the adjacent adrenal cortex tissue. LDL-R, ACAT1/2, HSL, DHCR24 were all significantly lower in clear than in compact tumor cells of APA. LDL-R was significantly lower and cholesterol/lanosterol ratio was significantly higher in KCNJ5- mutated than non-KCNJ5- mutated APAs. We demonstrated SR-B1 mediated selective uptake of cholesterol ester and de novo cholesterol synthesis were both enhanced in APAs. In addition, cholesterol uptake and metabolism were different between clear and compact tumor cells. KCNJ5- mutated APAs were predominantly composed of clear tumor cells containing abundant cholesteryl ester but less activated LDL-R mediated uptake and increased de novo synthesis. Those findings above indicated their more pronounced functional deviation from the normal ZG cells in terms of their steroidogenic and intracellular cholesterol metabolism.

Multi-step Phase Transformation from Metal-Organic Frameworks to Inorganic Compounds for High-Purity Th(IV) Generation.

The generation of high-purity thorium is the precondition for next-generation nuclear energy; however, this remains a challenging task. To this end, we present herein an ultrasimple technique with the combination of crystallization plus phase transformation. Crystallization into ECUT-68 is found to show almost 100% selective uptake of Th(IV) over rare earth and UO22+ ions, while multistep phase transformation from metal-organic frameworks (MOFs) to inorganic compounds is found to directly generate inorganic Th(IV) compound and then Th(IV) solution, suggesting its superior application in the generation of high-purity thorium.

Targeted Nanoparticles to Mitigate Radiation‐Induced Blood‐Brain Barrier Disruption and Cognitive Impairment

BackgroundUp to 90% of brain cancer survivors develop radiation‐induced cognitive dysfunction following treatment. Damage to neurovascular endothelium contributes to cognitive decline through increased blood‐brain barrier (BBB) permeability. In our preliminary studies of endothelial cells (ECs) and mice, increased mitochondrial reactive oxygen species (mtROS), inducing heightened mitochondrial DNA (mtDNA) damage and release as cell‐free DNA are detected following irradiation (IR). This cell‐free mtDNA is known to activate Toll‐like receptor 9 (TLR9), triggering an immune response and further ROS. These endothelial responses are prevented with TLR9 inhibition and mtROS scavenging, suggesting a key role for TLR9 in sustained IR‐induced endothelial damage and dysfunction.Here, we posit that specific inhibition of TLR9 in cerebral ECs during radiation treatment will prevent subsequent BBB permeability and cognitive decline. Thus, the objective of this study is to examine the role of TLR9 in IR‐induced cognitive decline using TLR‐specific loaded nanoparticles (NP).Methods and ResultsTo target TLR9 in irradiated ECs, poly (lactic‐co‐glycolic acid)‐based NP coated with cyclic Arg‐Gly‐Asp (cRGD)‐peptide were designed and loaded with TLR9 inhibitor (ODN‐2088, 2.23ug/mg particle). cRGD‐peptide is a ligand for integrin αvβ3, which is highly expressed in ECs post‐IR. cRGD‐NP loaded with coumarin‐6 were used to first evaluate specificity in vitro and in vivo. ECs 24h post‐IR (4 Gy) displayed higher fluorescence than non‐IR, indicating selective uptake. Moreover, in C57Bl6 mice 24h post unilateral cerebral IR (12Gy) with cRGD‐NP, uptake accumulated in endothelium of the IR hemisphere.Mice were administered NP‐ODN‐2088 or empty NP (3mg injection) and subjected to IR as described above. 30 days post‐IR, they were tested for memory and learning ability using the Novel Object Recognition test. IR induced a significant impairment in the memory ability of empty NP treated mice compared to NP‐ODN‐2088. BBB permeability was analyzed in the same mice 30 days post‐IR with immunohistochemistry using anti‐mouse IgG. Significant BBB permeability was detected in the IR hemisphere of empty NP mice compared to the non‐IR hemisphere. However, the IR hemisphere of NP‐ODN‐2088 mice showed attenuated permeability compared to empty NP treated mice.ConclusionInhibition of TLR9 in irradiated ECs was observed to protect against BBB disruption and cognitive decline. These data support a pathway of radiation‐induced endotheliopathy through which TLR9 activation links vascular mitochondrial injury to neuropathology. Currently there are no pharmacological options for treating radiation‐induced normal tissue injury and targeting TLR9 poses a promising strategy.

Speciality commercial ion exchange resins for use in nuclear industries for antimony removal: A systematic study

Antimony, a metalloid, is present in effluents generated in diverse industries. Antimony is of high concern in nuclear industries in particular due to the presence of its active isotopes. Safe management of such antimony containing effluents is a crucial problem which currently lacks viable solution. One of the reasons is the lack of availability of well-studied antimony removal agents. In this context, three commercially available speciality ion exchange resins (Tulsion® CH-87, CH-90 and CH-99) were evaluated for their antimony removal ability. Among the three resins evaluated, Tulsion® CH-99, a polyhydroxy amine-based resin, showed favourable results and its antimony binding properties were studied in detail. Tulsion® CH-99 showed fast uptake kinetics, selectivity, and antimony removal under wide solution pH conditions. Saturation capacities obtained were found to be 83 mg.g−1 (0.68 mmol.g−1) for Sb(V) and 73.1 mg.g−1 (0.6 mmol.g−1) for Sb(III). Batch and column studies carried out with simulated decontamination and reprocessing effluents of nuclear industry showed selective antimony uptake. Antimony uptake from typical reprocessing effluent (referred to as High Level Waste (HLW)), which has highly acidic and complex matrix (3 M HNO3 and a suite of competing ions such as Cr(VI)), demonstrated the high stability and antimony selectivity of the investigated resin.

Novel HDL mimicking targeted drug delivery system for the treatment of Ewing Sarcoma

PurposeSince their discovery as antitumor agents, anthracycline drugs such as doxorubicin have remained mainstays as an important class of chemotherapy for the treatment of a wide range of cancers including pediatric malignancies like Ewing Sarcoma (EWS). Unfortunately, their usage is limited due to cumulative dose‐dependent cardiotoxicity. Targeted drug delivery could be an important option to circumvent this problem.Experimental designOur laboratory has developed a novel reconstituted HDL drug delivery system comprised of Myristic acid conjugated Apo AI mimicking 5A peptide (Myr5A). We used a hydrophobic derivative of doxorubicin, N‐Benzyladriamycin‐14‐valerate (AD198) to engineer formulations of Myr5A‐AD198. Physico‐chemical characterization including size, zeta potential and entrapment efficiency was determined. Cytotoxic effectiveness of this formulation was tested in Ewing Sarcoma cells A673 and Cardiomyocytes, H9c2 in 2D and 3D spheroid model using CCK‐8 assays. Using Myr5A based formulation‐containing BODIPY; mechanism of uptake of payload was demonstrated by imaging. In addition, we investigated Biodistribution and payload retention in EWS tumors in xenograft NOG mice with EWS tumor model.ResultsFormulation of the Myr5A‐AD198 was stable and non‐leaky with payload entrapment efficiency of 47.6 ± 3.2%. The nanoparticles were spherical with average size of 47 ± 12 nm as observed by transmission electron microscopy (TEM). Cytotoxicity assays demonstrated that IC50 values of Myr5A‐AD198 formulation was 2.8 ± 0.4 times more effective than free AD198 in EWS cells. On the other hand, 3 times more dose was required for Cardiomyocytes with Myr5A‐AD198 formulation as compared to free AD198. Blocking the Scavenger Receptor type B1 (SR‐B1) receptors, resulted in inhibition of the uptake of payload in Myr5A formulation. Subcutaneous injection of Myr5A‐IR 780 dye in xenograft NOG mice indicated the retention of payload for up to 72 hours in tumor.ConclusionThese preclinical studies indicated a great translational potential of Myr5A‐AD198 formulation for the treatment of EWS patients due to its selective uptake mechanism and cardio‐protective effect. Longer retention of the drug in tumors as well as lower dose requirement compared to free drug gives an additional advantage. In future, the Myr5A based technology shows promise for personalized treatment options in EWS and other type of cancers as well.

Insights into the role of N‐linked glycosylation in directing plasma membrane localization of GPCRs expressed in Saccharomyces cerevisiae

Glycosylation is the biochemical process of the attachment of sugar moieties or carbohydrates to proteins during co‐translational or post‐translational modification (PTM). It is one of many types of protein modifications that naturally occurs during the process of protein expression in organisms like Saccharomyces cerevisiae (Baker’s yeast). For natively expressed proteins, glycosylation can be critical for proper protein processing and can also be important for the production of proteins in a stable and biologically active state. For proteins that are non‐natively, or heterologously, expressed in these organisms, glycosylation can lead to improper processing and ultimately produce proteins with little to no biological relevance. This proves to be an undesirable effect for the elucidation of protein structure. However, large quantities of protein are required for structural analysis, presenting a significant obstacle for structural biologists and those who use heterologous expression as a means to acquire large quantities of protein. This problem becomes significantly more challenging for membrane proteins.Membrane proteins are an elusive class of biomolecules that reside or closely associate with the lipid bilayers of cells and encompass transporters, receptors and channel pores, to name a few. They play an intrinsic role in maintaining proper cell function including signaling and selective uptake of extracellular ions and small molecules. G‐protein coupled receptors (GPCRs) constitute one of the largest groups of membrane proteins across the plant and animal kingdoms. Despite being of scientific and medical interest, GPCRs and many integral membrane proteins are notoriously difficult to isolate and work with because of their hydrophobicity, structural flexibility and instability in the absence of the cell membrane. Optimized experimental conditions often vary from protein to protein and necessitate a systematic approach to achieve. This typically requires labor and resource intensive efforts. The goal of this work is to uncover new insights into the role of post‐translational processing and protein localization in the cell. Using a combination of fluorescence microscopy and bioinformatics we formulated an approach to investigate the effects of N‐linked glycosylation on plasma membrane localization of GPCRs expressed in S. cerevisiae. We postulate a critical link between plasma membrane localization and expression of “ligand active” or structurally relevant GPCRs. Previous studies of the human adenosine A2A receptor (hA2AR) show it readily localizes to the plasma membrane during expression in yeast, while the human dopamine D2 receptor (hD2R) does not. A sequence comparison of the two reveals three putative N‐linked glycosylation sites at the N‐terminal extracellular region of hD2R which is lacking in hA2AR. Using a chimera of these two receptors prepared with a C‐terminal GFP tag, we show the chimera does not traffic to the plasma membrane similarly to full‐length hA2AR, suggesting N‐linked glycosylation strongly influences functional high‐level expression of GPCRs and possibly other membrane proteins in yeast.

Mechanically interlocked molecular architectures of valinomycin as cancer targeted prodrugs

AbstractMacrocyclic drugs are promising agents for treating a variety of diseases. However, these compounds usually present delivery limitations, such as low tissue selectivity and poor cellular uptake, which may impair efficacy and clinical translation. Here, we propose a molecular machine approach for delivering macrocyclic drugs based on their assembly into bioactive rotaxanes. To prove this concept, we use the extremely toxic macrocycle valinomycin (Val) as the host molecule, and identify dihydralazine (Dihyd) as a guest molecule after screening several guest compounds. The Val‐Dihyd complex is mechanically interlocked by capping one hydrazide group in Dihyd with fluorescein isothiocyanate (FITC) and the other with a Y‐shape branched poly(ethylene glycol) (PEG) via a pH‐sensitive hydrazone bond. Thus, the Val‐loaded rotaxanes (Vrot) are stable at physiological pH, but release Val at mild acidic conditions mimicking intratumoral and endosomal environments. In vitro studies revealed Vrot is less cytotoxic than free Val in pancreatic cancer cells, while modifying Vrot with cyclic arginine‐glycine‐aspartic acid (cRGD) peptides promotes the cytotoxicity by enhancing cellular uptake. These results indicate the potential of rotaxanes of macrocyclic drugs for generating cancer targeted prodrugs.

Trace removal of benzene vapour using double-walled metal–dipyrazolate frameworks

In principle, porous physisorbents are attractive candidates for the removal of volatile organic compounds such as benzene by virtue of their low energy for the capture and release of this pollutant. Unfortunately, many physisorbents exhibit weak sorbate–sorbent interactions, resulting in poor selectivity and low uptake when volatile organic compounds are present at trace concentrations. Herein, we report that a family of double-walled metal–dipyrazolate frameworks, BUT-53 to BUT-58, exhibit benzene uptakes at 298 K of 2.47–3.28 mmol g−1 at <10 Pa. Breakthrough experiments revealed that BUT-55, a supramolecular isomer of the metal–organic framework Co(BDP) (H2BDP = 1,4-di(1H-pyrazol-4-yl)benzene), captures trace levels of benzene, producing an air stream with benzene content below acceptable limits. Furthermore, BUT-55 can be regenerated with mild heating. Insight into the performance of BUT-55 comes from the crystal structure of the benzene-loaded phase (C6H6@BUT-55) and density functional theory calculations, which reveal that C–H···X interactions drive the tight binding of benzene. Our results demonstrate that BUT-55 is a recyclable physisorbent that exhibits high affinity and adsorption capacity towards benzene, making it a candidate for environmental remediation of benzene-contaminated gas mixtures.

Diamond in the rough: Polishing waste polyethylene terephthalate into activated carbon for CO2 capture

The scientific community has believed the potential of waste PET plastics as an effective carbon precursor, however, developing PET-derived activated carbons (PETACs) for a specific application is still a challenge we are facing. To overcome the limitation, a whole chain from development method screening to experiments design, finally to sample optimization, for a sample with promising performance, is proposed in this work. By employing PETACs as CO2 adsorbents, the waste PET plastics, which we believed the “diamond in the rough”, have been polished successfully. Therewith the problems of plastic pollution and the greenhouse effect could be simultaneously solved. The first half part of this paper is a mini review: the PETACs development methods were reviewed and the most suitable solution to develop CO2 adsorbent, i.e., the two-step chemical activation method, was selected. In addition to that, the necessary procedure variables and their value range were determined. In the second half part, the central composite design method was applied for experiments design in which the procedure variables obtained were regarded as the independent indicators (factors here) while the performance indicators, including yield, CO2 adsorption uptake, and CO2 over N2 selectivity, were treated as the dependent indicators (responses here). The responses were obtained through the characterization of the samples developed and statistical analysis could be applied to reveal the relations between the factors and responses. A high-value PETAC, P600K600-1.5, with the highest gas selectivity (22.189) and decent CO2 adsorption uptake (3.933 mmol/g) was successfully designed.

What the Tortoise Says about Statutory Interpretation: The Semantic Canons of Construction Do Not Tip the Balance

Abstract Karl Llewellyn’s critique of the canons of statutory interpretation led to a decline in their use for several decades. His critique, however, faced sustained resistance from some corners of the academy and the judiciary. Although this resistance has had only a selective uptake, it animated a gradual revival of the canons and brought the state of scholarship to an impasse that is for the most part partisan. In this article, I examine the semantic canons from a deeper level and argue that a universal assumption about them is false. Said assumption is that, although not dispositive, the semantic canons at least offer some reasons in favour of or against a candidate interpretation. Inclinations to rely on the semantic canons are also based on this assumption, although it is an assumption that the critics of the canons also share. I argue that this assumption is false because the semantic canons are a class of rules that are by nature not reason-giving. This provides a new ground against giving the semantic canons deliberative weight in questions of statutory interpretation.

Induction of apoptosis in human colorectal cancer cells by nanovesicles from fingerroot (Boesenbergia rotunda (L.) Mansf.).

Colorectal cancer is the leading cause of cancer-related deaths worldwide, warranting the urgent need for a new treatment option. Plant-derived nanovesicles containing bioactive compounds represent new therapeutic avenues due to their unique characteristics as natural nanocarriers for bioactive molecules with therapeutic effects. Recent evidence has revealed potential anticancer activity of bioactive compounds from Boesenbergia rotunda (L.) Mansf. (fingerroot). However, the effect and the underlying mechanisms of fingerroot-derived nanovesicles (FDNVs) against colorectal cancer are still unknown. We isolated the nanovesicles from fingerroot and demonstrated their anticancer activity against two colorectal cancer cell lines, HT-29 and HCT116. The IC50 values were 63.9 ± 2.4, 57.8 ± 4.1, 47.8 ± 7.6 μg/ml for HT-29 cells and 57.7 ± 6.6, 47.2 ± 5.2, 34 ± 2.9 μg/ml for HCT116 cells at 24, 48, and 72 h, respectively. Interestingly, FDNVs were not toxic to a normal colon epithelial cell line, CCD 841 CoN. FDNVs exhibited selective uptake by the colorectal cancer cell lines but not the normal colon epithelial cell line. Moreover, dose- and time-dependent FDNV-induced apoptosis was only observed in the colorectal cancer cell lines. In addition, reactive oxygen species levels were substantially increased in colorectal cancer cells, but total glutathione decreased after treatment with FDNVs. Our results show that FDNVs exhibited selective anticancer activity in colorectal cancer cell lines via the disruption of intracellular redox homeostasis and induction of apoptosis, suggesting the utility of FDNVs as a novel intervention for colorectal cancer patients.

Endocytosis Involved d-Oligopeptide of Tryptophan and Arginine Displays Ordered Nanostructures and Cancer Cell Stereoselective Toxicity by Autophagy.

Owing to their self-aggregation propensity and selective interaction with the anionic membranes, the peptides rich in tryptophan (Trp) and arginine (Arg) are considered for the development of novel anticancer therapeutics. However, the structural insights from the perspective of backbone chirality and spatial orientation of side chains into the selective toxicity of peptides are limited. Here, we investigated the selectivity and cellular uptake of HHC36, a Trp/Arg-rich nonapeptide, and its d-enantiomer (allDHHC36) and a retroinverso analogue in the lung A549 and breast MDA-MB-231 cancer cells. We realized that the d-peptides can specifically induce autophagy at nontoxic concentrations only in the A549 cells supported from the LC 3-II immunostaining expression in the vicinity of the nucleus and the ultrastructural analysis revealing the autophagosome formation. The autophagic flux was also remarkable in the cells exposed to d-peptides at a far lower concentration in synergism with doxorubicin (DOX). In marked contrast, nonselective cell death was observed only if a high amount of HHC36 was applied. HHC36 tended to irregular collagen-like fibrils relative to allDHHC36 that distinctly formed higher-order coiled nanostructures. Interestingly, the short d-peptide fragments were generated in a harsh oxidative condition. Compared with the direct membrane transduction of HHC36, the entry of d-peptides into the lung cancer cells was controlled by endocytosis through the contribution of heparan sulfate proteoglycans (HSPGs) and cholesterol (CHO). However, both l- and d-peptides feasibly crossed the membrane and localized inside the S-phase-arrested cell nucleus. This suggested the likelihood of peptide intercalation with DNA that might differently appear in selective and/or nonselective deaths. These results unraveled the d-handedness-selective toxicity of a self-assembling Trp/Arg-rich sequence that is dependent on the cell type from the aspects of the density of anionic charges and CHO in the outer leaflet of the plasma membrane, as well as the intracellular redox imbalance that may drive the formation of toxic peptide nanostructure fragments.

Exploring ITM2A as a new potential target for brain delivery

BackgroundIntegral membrane protein 2A (ITM2A) is a transmembrane protein expressed in a variety of tissues; little is known about its function, particularly in the brain. ITM2A was found to be highly enriched in human brain versus peripheral endothelial cells by transcriptomic and proteomic studies conducted within the European Collaboration on the Optimization of Macromolecular Pharmaceutical (COMPACT) Innovative Medicines Initiative (IMI) consortium. Here, we report the work that was undertaken to determine whether ITM2A could represent a potential target for delivering drugs to the brain.MethodsA series of ITM2A constructs, cell lines and specific anti-human and mouse ITM2A antibodies were generated. Binding and internalization studies in Human Embryonic Kidney 293 (HEK293) cells overexpressing ITM2A and in brain microvascular endothelial cells from mouse and non-human primate (NHP) were performed with these tools. The best ITM2A antibody was evaluated in an in vitro human blood brain barrier (BBB) model and in an in vivo mouse pharmacokinetic study to investigate its ability to cross the BBB.ResultsAntibodies specifically recognizing extracellular parts of ITM2A or tags inserted in its extracellular domain showed selective binding and uptake in ITM2A-overexpressing cells. However, despite high RNA expression in mouse and human microvessels, the ITM2A protein was rapidly downregulated when endothelial cells were grown in culture, probably explaining why transcytosis could not be observed in vitro. An attempt to directly demonstrate in vivo transcytosis in mice was inconclusive, using either a cross-reactive anti-ITM2A antibody or in vivo phage panning of an anti-ITM2A phage library.ConclusionsThe present work describes our efforts to explore the potential of ITM2A as a target mediating transcytosis through the BBB, and highlights the multiple challenges linked to the identification of new brain delivery targets. Our data provide evidence that antibodies against ITM2A are internalized in ITM2A-overexpressing HEK293 cells, and that ITM2A is expressed in brain microvessels, but further investigations will be needed to demonstrate that ITM2A is a potential target for brain delivery.

Molecular-level understanding of highly selective heavy rare earth element uptake by organophosphorus modified MIL-101(Cr)

Selective separation of rare earth elements (REEs) from solutions of mixed heavy and light metals by solid adsorbents is an important challenge in the fields of water treatment and metal recovery. The main challenge is water instability of many adsorbents, specifically metal–organic frameworks (MOFs), and their low selectivity. Grafting particular organophosphorus compounds (OPCs) on the MIL-101(Cr) MOF can provide both stability and selectivity. When the tributyl phosphate (TBP), bis(2-ethylhexyl) hydrogen phosphate (D2EHPA or HDEHP) and bis(2,4,4-trimethylpentyl)phosphinicacid (Cyanex®-272) OPCs are grafted and applied to mixed-metal aqueous solutions containing Co2+, Ni2+, Cu2+, Zn2+, Nd3+, Gd3+ and Er3+, MIL-101(Cr) offers high selectivity towards the Nd3+, Gd3+ and Er3+ REEs (with stronger affinity towards Er3+). However, the underlying chemistry is unknown and the factors leading to the selectivity remain poorly understood. To uncover the key molecular-level factors, we performed state-of-the-art computational simulations using a combination of high-level density functional theory (DFT), semi-empirical calculations, and configurational sampling of the metal ion-MOF binding modes in aqueous solutions. Our simulation study reproduced the available experimental results, in addition to determining the contributing intermolecular interactions, uptake modes and the most significant structural features for improving selectivity towards the REEs. Therefore, our most important result is rationalization of the mechanism of REE separation by OPC-grafted MOFs using quantum mechanical and electrostatic principles. The results provide guidelines for synthesis of OPC-grafted MIL-101(Cr) structures with enhanced selectivity and stability. Moreover, an efficient computational framework is proposed to facilitate comprehensive modeling of similar systems.

Smart releasing CuS/ZnS nanocomposite dual drug carrier and photothermal agent for use as a theranostic tool for cancer therapy

Multifunctional nanoparticles consisting of different therapeutic modalities and potential for imaging could hold promise to revolutionize cancer treatment and management. In this study, we have reported the synthesis of multifunctional CuS–ZnS nanocomposites modified in situ for targeted cancer therapy. CuS element of the nanocomposite enabled near-infrared light responsive photothermal therapy, whereas ZnS showed potential for photoluminescence. Successful nanocomposite formation was confirmed by UV–Visible spectroscopy, inductively coupled plasma atomic emission spectroscopy and energy-dispersive X-ray spectroscopy. These nanocomposites were coated with chitosan by exploiting electrostatic interactions as was confirmed by zeta potential analysis and FTIR spectroscopy. Chitosan also allowed encapsulation of hydrophilic and hydrophobic drugs with encapsulation efficiencies of 98% and 42% respectively. Release profiles of the drugs indicated pH dependent behavior and zero order kinetics. In vitro studies demonstrated selective uptake in HeLa cells, biocompatibility and haemocompatibility. NIR absorption of the nanocomposites led to high photothermal conversion efficiency (∼40%) which translated into thermal ablation of 80% MCF-7 cells in vitro. In vivo assessments in a 4T1 model showed significant reduction in tumors when treated with the nanocomposite. These results demonstrated the potential application of the nanocomposite for chemo-photothermal therapy in a targeted and stimulus responsive manner.

HDL Receptor in Schistosoma japonicum Mediating Egg Embryonation: Potential Molecular Basis for High Prevalence of Cholesteryl Ester Transfer Protein Deficiency in East Asia.

Schistosomiasis is a life-threatening parasitic disease caused by blood flukes, Schistosomes. In its intestinal type, the parasites reside in visceral/portal veins of the human hosts and lay eggs to excrete in feces via intestinal tracts, and some of the aberrant eggs plug into the liver via the portal blood flow. Ectopic growth of these eggs causes fatal granulomatosis and cirrhosis of the liver. The parasites ingest nutrients from the host blood plasma by using nonspecific and specific transport via their body surface and alimentary tracts. It is especially important for the female adults to obtain lipid molecules because they synthesize neither fatty acids nor sterols and yet produce egg yolk. Low-density lipoprotein receptors have been identified in the body of the Schistosomes but their functions in the parasite life cycle have not clearly been characterized. On the other hand, CD36-related protein was identified in the body and the eggs of Asian blood fluke, Schistosoma japonicum, and characterized as a molecule that mediates selective uptake of cholesteryl ester from the host plasma high-density lipoproteins (HDLs). This reaction was shown crucial for their eggs to grow to miracidia. Interestingly, abnormal large HDL generated in lack of cholesteryl ester transfer protein (CETP) is a poor substrate for this reaction, and, therefore, CETP deficiency resists pathogenic ectopic growth of the aberrant parasite eggs in the liver. This genetic mutation is exclusively found in East Asia, overlapping with the current and historic regions of Schistosoma japonicum epidemic, so that this infection could be related to high prevalence of CETP deficiency in East Asia.

Growth of cobalt based-coordination polymer on the surface of filter paper for fast up-taking of Congo red by simple filtration

The grafting of coordination polymers (CPs) to other compounds is a great technique to produce advanced materials with favored properties. Especially, conjugation of the CPs with flexible materials such as filter paper (FP) is anticipated to prepare valuable adsorbents for separation purposes. Herein, a Co-based coordination polymer (Co-CP) with 2-aminobenzene-1,4-dicarboxylic acid (NH2-BDC) as a linker was grown on the surface of functionalized FP to attain CP-paper composite. Chloroacetic acid was used as a surface modifier for improving the adaptability and connection between Co-CP and FP. The terminal COO− groups on the surface of carboxylated filter paper (CFP) operated as connecting groups to coordinate Co2+ cations. Layer-by-layer (LbL) growth ensured complete and homogeneous distribution of the CP on the CFP. The exploited strategy to functionalize FP revealed efficient, selective, and rapid uptake of model pollutants (more than 90% for Congo red, CR) through the simple filtration of CR solution on the obtained CFP/Co-CP as a CP-paper. The kinetics and mechanism and of the uptake by CFP/Co-CP were also demonstrated by the Langmuir isotherm and the pseudo-second-order model represented a very good match with experimental data. The CFP/Co-CP can be simply recovered and reused four times without effective loss of its dye uptake ability.

Evaluation of the distribution and excretion of [14C]-inclisiran following single subcutaneous administration in cynomolgus monkeys

Inclisiran is a small interfering RNA molecule that was designed to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels by inhibiting proprotein convertase subtilisin/kexin type 9 synthesis in the liver. This study aimed to characterize the tissue distribution and excretion of inclisiran after dosing in monkeys.A single 20 mg/kg subcutaneous injection of [14C]-inclisiran was administered to 12 male cynomolgus monkeys. Plasma concentrations and tissue binding parameters for inclisiran were assessed up to 42 days after injection using liquid scintillation of blood samples and tissue homogenates, as well as quantitative whole-body autoradiography.Radioactivity was highest in the liver at all time points from 24 h onward and remained elevated throughout the entire study period. Radioactivity was also detected in the kidneys and bladder wall, returning to low levels by 24 h. The concentration of radioactivity in the liver (402.97 μg equivalent/g) was 15.7-fold higher than in the kidneys (25.70 μg equivalent/g). Very low amounts of radioactivity were detected in all other tissues examined. The highest radioactivity in tissue homogenates was in the liver and kidney pyramid (327 and 351 μg equivalent/g, respectively).This study confirmed the selective uptake of inclisiran by the liver, indicating that the N-acetylgalactosamine linker allows for selective uptake via the asialoglycoprotein receptors expressed on hepatocytes compared with other tissues that lack asialoglycoprotein receptors. The long tissue retention in the liver supports the infrequent, biannual dosing schedule for inclisiran in the clinic and the temporal disconnect between short-term systemic exposure and sustained lowering of LDL-C.

Poly(vinylbenzyl Pyridinium Salts) as Novel Sorbents for Hazardous Metals Ions Removal.

Novel efficient complexing resins—poly(vinylbenzyl pyridinium salts) fabricated through poly(vinylbenzyl halogene-co-divinylbenzene) quaternization of N-decyloxy-1-(pyridin-3-yl)ethaneimine and N-decyloxy-1-(pyridin-4-yl)ethaneimine—were tested as adsorbents of Pb(II), Cd(II), Cu(II), Zn(II), and Ni(II) from aqueous solutions. The structure of these materials was established by 13C CP-MAS NMR, X-ray photoelectron spectroscopy, elemental analysis, and Fourier transform infrared spectroscopy, as well as thermogravimetric and differential thermal analyses. The textural properties were determined using scanning electron microscopy and low-temperature N2 sorption. Based on the conducted sorption studies, it was shown that the uptake behavior of the metal ions towards novel resins depended on the type of functionalities, contact time, pH, metal concentrations, and the resin dosage. The Langmuir model was investigated to be the best one for fitting isothermal adsorption equilibrium data, and the corresponding adsorption capacities were predicted to be 296.4, 201.8, 83.8, 38.1, and 39.3 mg/g for Pb(II), Zn(II), Cd(II), Cu(II), and Ni(II), respectively. These results confirmed that owing to the presence of the functional pyridinium groups, the resins demonstrated proficient metal ion removal capacities. Furthermore, VBBr-D4EI could be successfully used for the selective uptake of Pb(II) from wastewater. It was also shown that the novel resins can be regenerated without significant loss of their sorption capacity.